The present invention relates to novel compounds which are protein kinase C inhibitors. methods for their preparation, intermediates therefor and pharmaceutical compositions comprising them.
Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine-specific protein kinases which play an important role in cellular growth control, regulation and differentiation.
Since the activation of PKC has been implicated in several human disease processes, including various forms of cancer, different forms of inflammatory and/or immunological disorders as well as some neurological disorders, inhibition of PKC could be of therapeutic value in treating these conditions.
Several classes of compounds have been identified as PKC inhibitors, e.g. isoquinoline sulphonamides, sphingosine and related sphingolipids, indolocarbazoles and bisindolyl-maleimides.
EP 0 328 026 describes the use of certain bisindolylmaleimides, a class of compounds related to the indolocarbazoles, in medicaments for the treatment of various conditions.
Baskakow et al.; SU 389096; 1973 describes 1,5 substituted diphenyl imidazolones although these are not suggested to be of any therapeutic potential.
Although PKC inhibitors are described in the prior art, there is a need for specific anti-inflammatory and immuno suppressive compounds, which are suitable for oral administration, and for inhalation. Furthermore. there is a need for such compounds, which are more soluble and less colored than the presently known PKC inhibitors.
The present invention provides kinase inhibitors that are particularly PKC inhibitors. methods for their preparation and intermediates used for their preparation.
The kinase inhibitors of the present invention are surprisingly more soluble and less colored than the kinase inhibitors, especially the PKC inhibitors, known in the prior art.
The present invention also provides the use of the compounds of the present invention for the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorders.
Also provided by the present invention are pharmaceutical compositions comprising a compound according to the present invention, as active ingredient, together with a pharmaceutically acceptable adjuvant, diluent or carrier.
The present invention provides compounds of formula (I): 
wherein:
Ar1 or Ar2 is an optionally substituted indole, and the other group is an optionally substituted aromatic or heteroaromatic group, suitably an optionally substituted bicyclic heteroaromatic group, preferably an optionally substituted indole.
X is O or S,
R is H, OH, NH2, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, and
R1 is H, C1-6alkyl, fluoro substituted C1-6alkyl, phenyl, benzyl, carboC1-6alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C1-6alkylcarbamoyl)
and salts and solvates thereof and solvates of such salts.
Preferred embodiments of formula (I) are compounds of formula (II), and (III) 
wherein:
Ar is an optionally substituted aromatic or heteroaromatic group,
X is O or S,
R is H, OH, NH2, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
R1 is H, C1-6alkyl, fluoro substituted C1-6alkyl, phenyl, benzyl, carboC1-6alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C1-6alkylcarbamoyl),
R2 is H, C1-6alkyl, benzyl, C1-3alkoxy substituted benzyl, hydroxy(C1-6)alkyl, hydroxy(C3-7)cycloalkyl, nitrile(C1-6)alkyl, azido(C1-6)alkyl, amino(C1-6)alkyl, amino(C3-7)cycloalkyl, aminomethyl(C3-7)cycloalkyl, amino(C5-7)cycloalkenyl, (mono- or di-C1-6alkyl) amino(C1-6)alkyl, benzylamino(C1-6)alkyl, (mono- or di-C1-6alkyl) amino(C3-7)cycloalkyl, (mono- or di-C1-6alkyl) aminomethyl(C3-7)cycloalkyl, (amino(C1-3)alkylphenyl)(C1-3)alkyl, amino(C1-3)alkylphenyl, guanidino(C1-6)alkyl, amidino(C1-6)alkyl, amidinothio(C1-6)alkyl, [N,N-di-(C1-6)alkyl]amidino(C1-6)alkyl, amidino(C1-3)alkylphenyl, [N,N-mono- or di-(C1-6)alkyl]amidino(C1-3)alkylphenyl, (N-benzyl)amidino(C1-3)alkylphenyl, (4-morpholinyl)imino(C1-3)alkylphenyl, benzimic acid methyl ester(C1-3)alkyl, hydroxy(C1-3)alkylamino (C1-6)alkyl, carboxy(C1-3)alkylamino (C1-6)alkyl, carboxymethyl(C1-3)alkylamino (C1-6)alkyl, amino(C1-3)alkyloxy (C2-6)alkyl, formamide(C1-6)alkyl, (N,N-dimethyl)imidoformamide(C1-6)alkyl, or a group of the formula
xe2x80x94(CH2)nxe2x80x94Het
in which
n is an integer of 0-6;
Z is carbonyl or methylene;
Het is an optionally substituted 5- or 6-membered heterocyclic group,
R3 and R5 are each independently H, halogen, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, hydroxy, amino, nitro, nitrile, and
R4 is H, C1-3alkyl or together with R2, forms an annulated ring which may be substituted by hydroxyC1-3alkyl, amidinothioC1-3alkyl, or aminoC1-3alkyl,
or a salt or solvate thereof or a solvate of a salt thereof.
Preferred embodiments of compounds of formula (II), and (III) are 
wherein:
Ar is an optionally substituted aromatic or heteroaromatic group,
X is O or S,
R is H, OH, NH2, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
R1 is H, C1-6alkyl, fluoro substituted C1-6alkyl, phenyl, benzyl, carboC1-6alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C1-6alkylcarbamoyl),
R2 is H, C1-6alkyl, haloC1-6alkyl, bensyl, C1-3alkoxy substituted bensyl, nitrileC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, (pyridinylmethyl)aminoC1-6alkyl, (mono- or di-C1-6alkyl)aminoC1-6alkyl, (mono- or di-C1-3haloalkyl)aminoC1-6alkyl, aminoC3-7cycloalkyl, (mono- or di-C1-6alkyl)aminoC3-7cycloalkyl, (aminoC3-7cycloalkyl)C1-3alkyl, (hydroxyC1-6alkyl)aminoC1-6alkyl, (aminoC1-6alkyl)aminoC1-6alkyl, (C1-6alkynyl)aminoC1-6alkyl, (bensyl)aminoC1-6alkyl, (mono- or di-C1-3alkoxy substituted bensyl)aminoC1-6alkyl, (aminoC1-3alkylphenyl)C1-3alkyl, (aminoC1-3alkylthiophenyl)C1-3alkyl, (aminoC1-3alkylpyridinyl)C1-3alkyl, guanidino C1-6alkyl, (guanidinoC1-3alkylphenyl)C1-3alkyl, amidinoC1-6alkyl or amidinothioC1-6alkyl or a group of the formula
xe2x80x94Zxe2x80x94(CH2)nxe2x80x94Het
in which
Z is carbonyl or methylene
n is an integer of 0-5, and
Het is an optionally substituted 5- or 6-membered heterocyclic group,
R3 and R5 are each independently H, halogen, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, hydroxy, amino, nitro, nitrile, and
R4 is H, C1-3alkyl or together with R2, forms an annulated ring which may be substituted by hydroxyC1-3alkyl, amidinothioC1-3alkyl, or aminoC1-3alkyl,
and salts and solvates thereof and solvates of such salts.
For compounds of formula (II) and (III), the following independent preferences apply:
Ar is an optionally substituted bicyclic aromatic or an optionally substituted bicyclic heteroaromatic group,
R is H
X is O
R1 is H or methyl; or if a fluoro substituted C1-6alkyl, is preferably CF3, 
when R4 is H, R2 is H, methyl, hydroxyC1-6alkyl, aminoC1-6alkyl, (mono- or di-C1-6alkyl)aminoC1-6alkyl, aminoC3-7cycloalkyl, (mono- or di-C1-6alkyl)aminoC3-7cycloalkyl, guanidino C1-6alkyl, amidinoC1-6alkyl or amidinothioC1-6alkyl,
when R2 and R4 together form an annulated ring, they together comprise 4 or 5 carbons,
R3 and R5 are independently H or methoxy.
In more preferred embodiments of formula (II) and (III), Ar comprises a single heteroatom selected from N, O and S.
In yet more preferred embodiments of formula (II) and (III), Ar is selected from benzothiophene, naphthyl, phenoxyphenyl, or an optionally substituted indolyl which if substituted is preferably substituted with aminopropyl, dimethylaminopropyl, aminobutyl, aminocyclopentyl, aminomethylbensyl, or amidinothiopropyl.
Preferred compounds according to the present invention include:
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-benzo[b]thoiphenyl-1,3-dihydroimidazol-2-one,
5-[1-(3-Aminopropyl)-3-indolyl]-1-(1-naphthyl)-1,3-dihydroimidazol-2-one,
5-[1-{3-(Aminomethyl)benzyl}-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,
5-[-1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-4-methyl-1,3-dihydroimidazol-2-one,
5-[1-(3-Amidinothiopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,
5-{1-[3-(N,N-Dimethylamino)propyl]-3-indolyl}-1-(3-indolyl)-1,3-dihydroimidazol-2-one; and
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-4-phenyl-1,3-dihydroimidazol-2-one;
and salts and solvates thereof and solvates of such salts.
Salts of the compounds of formula (I) according to the invention are preferably pharmaceutically acceptable salts. Other salts may however be useful in the preparation of the compounds or in the preparation of pharmaceutically acceptable salts.
Pharmaceutically acceptable salts of compounds of the present invention are preferably those well known in the art as being suitable and are preferably acid addition salts and more preferably acetate salts or trifluoroacetate salts.
Solvates of the compounds or salts of the present invention are conveniently hydrates, such as monohydrates or dihydrates.
Compounds of the present invention include all pure stereoisomers and all mixtures thereof.
Preparation of the Compounds of the Invention
Compounds of formula (I) may be synthesised in the following ways:
(A) Compounds of formula (I) may be synthesised by converting a compound of formula (I) to a salt, especially a pharmaceutically acceptable salt, thereof, or vice versa; or converting a salt, especially a pharmaceutically acceptable salt, of a compound of formula (I) into a different salt, especially a pharmaceutically acceptable salt.
(B) Compounds of formula (I) may be synthesised by intramolecular condensation of a compound of formula (IV): 
in which X, R, R1, Ar1 and Ar2 are as defined for formula (I).
The condensation may be performed under acidic conditions, preferably using acetic acid or scandium(III)trifluoromethanesufonate, at a temperature in the range of from about 90xc2x0 C. to about 130xc2x0 C., suitably from 100xc2x0 C. to 120xc2x0 C. and preferably at about 100xc2x0 C., for a period of time in the range of from about 5 min to about 6 h, suitably from 15 min to 3 h, preferably for about 1 h.
Compounds of formula (II) and (III) in which X is O may be synthesised by intramolecular condensation of a compound of formula (V) or (VI) respectively: 
in which Ar, R and R1-R5 are as defined for formula (II) and (III).
Compounds of formula (I), (II) or (III) carrying one or more functional groups which might be sensitive to or interfere with the reaction conditions in process (B), can be prepared using a corresponding compound of formula (I), (II) or (III) respectively, but in which the functional groups are suitably protected, followed by subsequent deprotection.
Functional groups that might be sensitive for or interfere with the reaction conditions in process (B), as well as suitable protecting groups and deprotecting methods, are evident to those skilled in the art.
Compounds of formula (II) or (III), in which at least one of R2 or Ar carries an amino, or hydroxy group; and pharmaceutically acceptable salts thereof, may be prepared by deprotecting a compound of formula (II) or (III), respectively, but in which at least one of R2 or Ar carries a protected amino or hydroxy group.
In the processes described above, the protecting groups and conditions for deprotection are well known to those skilled in the art. Suitable protecting groups for amino groups are e.g. phthaloyl groups and the deprotecting agent may be methylamine in e.g. water. The deprotecting step may be carried out in a suitable solvent, e.g. tetrahydrofuran at about 10-30xc2x0 C., e.g. for about 5 hours. The hydroxy groups may be protected as their corresponding acetoxy groups and the deprotecting agent may be methylamine in e.g. water. The deprotecting step may be carried out in a suitable solvent, e.g. tetrahydrofuran at about 10-30xc2x0 C., e.g. for about 16 hours.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T. W. Greene and P. G. M. Wutz, Wiley-Interscience (1991).
The starting materials for the above processes (A) and (B) may be made by the methods described herein and particularly by those methods set out in the Examples or by methods analogous thereto. Other conventional methods for making the starting materials will be evident to those skilled in the art.
Compounds of formula (V) and (VI) in which R2 is not H may be synthesised by alkylation with an optionally substituted alkylating agent, of compounds of formula (VII) and (VIII), respectively. The alkylating agent may be an alkyl halide, or an alkyl halide carrying a dialkyl amino group, or an alkylating agent carrying a protected amino or hydroxy group. 
in which Ar, R, R1-R5 are as defined for formula (II) and (III).
Compounds of formula (V) and (VI), in which Ar, R, R1-R5 are as defined for formula (II) and (III), provided that R2 is not H, may also be prepared by reaction of the appropriate isocyanate with a relevant alpha-ketoamine, wherein either the isocyanate or the alpha-ketoamine carries the R2 group, using standard techniques.
Compounds of formula (VII) and (VIII) may be prepared by reaction of the appropriate isocyanate with a relevant alpha-ketoamine using standard techniques.
Compounds of formula (II) in which X is O, R2 is alkyl and Ar is an indole, substituted on the indole nitrogen with an alkyl carrying an amino or hydroxy group, may be prepared by deprotecting a compound of formula (IX) 
in which R6 is an alkyl carrying a protected amino or hydroxy group, and R1, R3, R4 and R5 are as defined for formula (II).
The protecting groups and conditions for the deprotection are the same as mentioned earlier.
Compounds of formula (IX) may be prepared by selective removal of a Troc group from a compound of formula (X) 
in which R2 is alkyl and R1, R3, R4 and R5 are as defined for formula (II),
followed by subsequent alkylation under standard conditions, with an alkyl carrying a protected amino or hydroxy croup. Selective deprotection of the Troc group may be carried out with cadmium in acetic acid and DMF.
Compounds of formula (X) may be prepared by introducing a Boc group, under standard conditions, to a compound of formula (II) but in which R is H and the Ar group is a Troc protected indole. Such a compound is prepared from a compound of formula (V), but in which R is H and the Ar group is a Troc protected indole.
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route. This will e.g. on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted.
Prodrugs and Intermediates
It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula (I), (II) and (III) which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Moreover, certain compounds of formula (I), (II) and (III) may act as prodrugs of other compounds of formula (I), (II) and (III).
All prodrugs of compounds of formula (I) are included within the scope of the present invention.
Novel intermediates as described hereinbefore and their use in the manufacture of other compounds of the present invention also form part of the invention. Thus, according to a further aspect of the invention there is provided compounds of formulae (V) to (X) as defined hereinbefore, or protected derivatives of any of these compounds.
Medical and Pharmaceutical Use
Also provided according to the present invention are compounds of the present invention for use in medical therapy; the use of compounds of the present invention in the manufacture of medicaments for use in medical therapy, and more particularly in the treatment of the conditions described herein; and methods of medical therapy comprising the administration of a therapeutically effective amount of a compound of the present invention to an individual requiring such therapy.
The term xe2x80x98medical therapyxe2x80x99 as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
The compounds of formula (I), (II) and (III) and salts, especially pharmaceutically acceptable salts, and solvates thereof, and solvates of such salts are useful because they demonstrate pharmacological activity. In particular they demonstrate activity as kinase inhibitors, especially PKC inhibitors, e.g. as is shown by their activity in the in vitro assays described in Granet, R. A. et al, Analyt. Biochem. 1987; 163, 458-463; Olsson, H. et al. Cell Signal 1989, 1, 405-410: and Chakravarthy, B. R. et al, Analyt. Biochem. 1991, 196, 144-150.
The compounds of the invention are indicated for use in the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorders; preferably for oral or topical treatment of inflammatory and/or immunological disorders, such as the oral or topical treatment of airway diseases involving inflammatory conditions, e.g. asthma, bronchitis; or atopic diseases, e.g. rhinitis or atopic dermatitis; inflammatory bowel diseases. e.g. Crohn""s disease or colitis; autoimmune diseases e.g. multiple sclerosis, diabetes, atherosclerosis, psoriasis, systemic lupus erythematosus or rheumatoid arthritis; malignant diseases, e.g. skin or lung cancer; HIV infections or AIDS; or for inhibiting rejection of organs/transplants. The compounds of the invention are also indicated for use in treatment of heart failure, and in treatment of diabetic patients with macular edema or diabetic retinopathy.
Pharmaceutical Preparations
The dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. The dosage will preferably be in the range of from 0.01 mg/kg to 10 mg/kg.
The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, e.g. formulations in the inhaler device known as the Turbuhaler(copyright); or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration, e.g. in the form of sterile parenteral solutions or suspensions, or by rectal administration, e.g. in the form of suppositories.
The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 xcexcm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (e.g. oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, e.g. lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose. mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatin capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler(copyright) in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound, with or without a carrier substance, is delivered to the patient.
For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol; a starch, e.g. potato starch, corn starch or amylopectin; a cellulose derivative; a binder, e.g. gelatin or polyvinylpyrrolidone, and/or a lubricant, e.g. magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatin, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatin capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatin capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.